Severe anemia is one of the deadliest complications in children infected with Plasmodium falciparum in sub- Saharan Africa. This anemia cannot be accounted for solely on the basis of destruction of parasitized RBCs. Therefore, the long-term objective of this application is to identify the pathogenic mechanisms that lead to severe malarial anemia and that involve destruction of uninfected RBCs. Children with severe malarial anemia have acquired deficiencies of RBC complement regulatory proteins (CRPs) (CRl and CD55) and the expression of these proteins is age-dependent, being lowest among children with the highest risk of anemia. Other reported abnormalities in children with severe malarial anemia are the excessive production of immune complexes (ICs), pro-inflammatory cytokines and nitric oxide (NO). Preliminary data indicate that ICs contribute to the inflammatory response during malaria infection and that RBC CRl plays a crucial role in modulating the production of pro-inflammatory cytokines and NO in response to ICs. We postulate the following: 1) RBCs of children with severe malarial anemia are more susceptible to complement-mediated lysis than those of children with uncomplicated malaria due to deficiencies in RBC CR1 and CD55. 2) The level of pro-inflammatory cytokine and NO produced during malaria infection is modulated by the capacity of RBCs to bind and remove immune complexes from circulation. 3) There are no qualitative differences between ICs formed in children with severe malarial anemia and those formed in children with uncomplicated malaria. In the present application we propose to test these hypotheses by carrying out case-control and cross-sectional studies to determine if RBCs of children with severe malarial anemia have increased susceptibility to complement-mediated lysis and decreased capacity to bind IC, and whether these parameters change as CRP expression changes with age. The studies proposed here will advance our understanding of the role of ICs and CRPs in the pathogenesis of severe malarial anemia, and of the nature of the ICs that form during malaria infection and their implications for the safety of future experimental malaria vaccines in children.